Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Neurite atrophy and synaptic loss initiate the onset of neuronal death, while the activated M1 microglia-induced neuroinflammatory microenvironment inhibits neurite regeneration and exacerbates neuronal loss. Thus, optimizing the brain microenvironment using small compounds through suppressing activated M1 microglia and promoting neurite regrowth might be an effective therapeutic strategy for AD. We found that hederagenin (HED), a naturally occurring triterpene compound, inhibited lipopolysaccharide-induced nitric oxide generation and downregulated expression of proinflammatory cytokines, such as tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6. Further investigation of primary microglia confirmed that HED inhibited Iba-1 positive M1 microglia. However, no changes were seen in CD206 positive M2 microglia polarization. HED remarkably suppressed phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells subunit p65 signaling. In addition, HED ameliorated Aβ25-35-induced neuritic atrophy and neuronal death. Therefore, HED might be a therapeutic candidate for AD.

阿尔茨海默氏病（AD）是一种进行性神经退行性疾病。神经突萎缩和突触丧失引发神经元死亡的发作，而活化的M1小胶质细胞诱导的神经炎症微环境抑制神经突再生并加剧神经元丧失。因此，通过抑制活化的M1小胶质细胞和促进神经突再生，使用小分子化合物优化大脑微环境可能是AD的有效治疗策略。我们发现，天然存在的三萜化合物hederagenin（HED）抑制脂多糖诱导的一氧化氮生成，并下调促炎细胞因子的表达，例如肿瘤坏死因子-α，白介素-1β（IL-1β）和IL-6。对原发性小胶质细胞的进一步研究证实，HED抑制了Iba-1阳性M1小胶质细胞。然而，CD206 M2小胶质细胞阳性未见极化变化。HED显着抑制了活化B细胞亚基p65信号转导的磷酸化核因子kappa-轻链增强子。此外，HED改善了Aβ25-35诱导的神经萎缩和神经元死亡。因此，HED可能是AD的治疗候选药物。